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The Journal of Neuroscience, March 1, 2000, 20(5):1746-1753
dCLOCK Is Present in Limiting Amounts and Likely Mediates Daily
Interactions between the dCLOCK-CYC Transcription Factor and the
PER-TIM Complex
Kiho
Bae1,
Choogon
Lee1,
Paul E.
Hardin3, and
Isaac
Edery2
1 Graduate Program in Microbiology and Molecular
Genetics and 2 Department of Molecular Biology and
Biochemistry, Rutgers University, Center for Advanced Biotechnology and
Medicine, Piscataway, New Jersey 08854, and 3 Department of
Biology and Biochemistry, University of Houston, Houston, Texas
77204-5513
In Drosophila melanogaster four circadian clock
proteins termed PERIOD (PER), TIMELESS (TIM), dCLOCK (dCLK), and CYCLE
(CYC/dBMAL1) function in a transcriptional feedback loop that is a core
element of the oscillator mechanism. dCLK and CYC are members of the
basic helix-loop-helix (bHLH)/PAS (PER-ARNT-SIM) superfamily of
transcription factors and are required for high-level expression of
per and tim and repression of
dClk, whereas PER and TIM inhibit dCLK-CYC-mediated transcription and lead to the activation of dClk. To
understand further the dynamic regulation within the circadian
oscillator mechanism, we biochemically characterized in
vivo-produced CYC, determined the interactions of the four
clock proteins, and calculated their absolute levels as a function of
time. Our results indicate that throughout a daily cycle the majority
of the dCLK present in adult heads stably interacts with CYC,
indicating that CYC is the primary in vivo partner of
dCLK. dCLK-CYC dimers are bound by PER and TIM during the late evening
and early morning, suggesting the formation of a tetrameric complex
with impaired transcriptional activity. Although dCLK is present in
limiting amounts and CYC is by far the most abundant of the four clock
proteins that have been examined, PER and TIM appear to interact
preferentially with dCLK. Our results suggest that dCLK is the main
component regulating the daily abundance of transcriptionally
active dCLK-CYC complexes.
Key words:
circadian rhythms; clock proteins; Drosophila; transcription; PAS; protein-protein
interactions
Copyright © 2000 Society for Neuroscience 0270-6474/00/2051746-08$05.00/0
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